Although their function in defense against neoplasia is yet incompletely understood, macrophages probably play a significant part in the rejection of tumors. Of importance to immunotherapy, this role can be augumented. We suggest macrophage cytotoxicity can be increased by altering their metabolism (activation). Equipping them with recognition factors specific for the target cells (such as antibody) could also increase their cytotoxicity. In a quantitative assay of macrophage cytotoxicity developed in this laboratory, we propose to test the above hypothesis by measuring the cytotoxicity of murine macrophages toward syngeneic tumors. The cytotoxicity of variously activated macrophages will be determined and compared. The studies will probe the relationship between activation and recognition, how these affect cytotoxicity, the cytotoxic specificity of the altered cells, and how the two can be altered. The studies also seek to define the metabolic properties of activation that confer heightened cytotoxicity. Factors including mode of activation, surface active agents, role of cyclic nucleotide that regulate the cytotoxicity of activation will be studied. Emphasis will be placed on seeking drugs that can pharmacologically increase macrophage cytotoxicity. Also studied are how carcinogens and tumors alter (depress) macrophage function. The long range strategy is to define simple means of altering macrophages, that can induce effective cytotoxicity in vitro and ultimately in vivo. The ultimate goal is development of a rational basis of immunotherapy that employs either simplified stimulants of macrophage function or infusions of macrophages altered for effective cytotoxicity. BIBLIOGRAPHIC REFERENCES: Adams, D.O.: The mononuclear phagocyte system: Human disorders and their evaluation. (Ann. Rev. Allergy, in press, 1977). Adams, D.O.: Therapeutic manipulation of the mononuclear phagocyte system. (Ann. Rev. All., in press, 1977).